INTRODUCTION — Protein intake may be inadequate in hemodialysis patients [1]. The hemodialysis procedure itself may adversely affect nutritional status by causing amino acid and albumin losses and by increasing protein catabolism via inflammation [2].
Low dietary protein intake and malnutrition are associated with increased risk of death among hemodialysis patients [3-5]. Some studies suggest that protein intake itself is an independent predictor of outcome [3,6]. Therefore, it is important to monitor protein intake, along with other measures of nutrition among these patients.
It is difficult to directly measure protein intake. A method that is commonly used to estimate protein intake is to measure the rate of increase in serum urea nitrogen levels between two hemodialysis treatments. This indirect marker of protein intake is referred to as the protein equivalent of nitrogen appearance (PNA) or protein catabolic rate (PCR). The PCR is used to assess dietary protein intake in dialysis patients.
This topic reviews the use of the PCR for the estimation of protein intake and recommendations for optimal protein intake for dialysis patients.
The assessment of overall nutritional status and treatment of malnutrition among hemodialysis patients is discussed elsewhere.
●(See "Assessment of nutritional status in patients on hemodialysis".)
●(See "Pathogenesis and treatment of malnutrition in maintenance hemodialysis patients".)
Optimal protein intake among peritoneal dialysis patients is discussed elsewhere.
●(See "Nutritional status and protein intake in peritoneal dialysis patients".)
OVERVIEW — The protein catabolic rate (PCR) reflects the amount of protein that is catabolized in excess of the amount of protein that is synthesized per day. In a person who is in steady state (ie, neither catabolic nor anabolic), the PCR reflects dietary protein intake [7].
Calculation — The PCR is calculated from the interdialytic appearance of urea in body fluids. The interdialytic appearance of urea is determined by measuring the blood urea nitrogen (BUN) at the end of one dialysis session and just prior to the start of the next dialysis session. Among patients who have low BUN, measuring the change in BUN between dialysis sessions (ie, the PCR) distinguishes adequate dialysis as a cause of low BUN from poor intake resulting from inadequate dialysis.
As an example, a low predialysis BUN could represent either a well-nourished patient who is adequately dialyzed or a patient who is malnourished due to poor appetite from inadequate dialysis. The PCR will distinguish between these possibilities.
The PCR is expressed as g per day. Usually, the PCR is normalized to the patient’s body weight (nPCR), which is expressed as g/kg per day.
The PCR in patients treated with hemodialysis is calculated by various urea kinetic modeling software programs. If a computer program is not available, the following simple formula will give a good estimate of the nPCR [8]:
(0.036 x ID rise in BUN x 24)
nPCR, in g/kg per day = 0.22 + —————————————————
ID interval (hours)
where the interdialytic (ID) rise in BUN is expressed in mg/dL. If, for example, the interdialytic rise in BUN is 50 mg/dL (18 mmol/L) and there are 44 hours from the end of one dialysis to the beginning of the next, then:
nPCR = 0.22 + ([0.036 x 50 x 24] ÷ 44) = 1.20 g/kg per day
The nPCR can also be calculated from the Kt/V (an index of urea removal during dialysis) and the average BUN [9].
Among patients with residual kidney function, total urea lost in the urine must also be measured from urine collected during the interdialytic period. Using this measurement, the following term is added to the equation for nPCR:
Urinary urea nitrogen (g) x 150
+ ———————————————————
ID interval (hours) x weight (kg)
where the urinary urea nitrogen is all of the urea nitrogen excreted in a urine collection obtained from the end of one dialysis to the beginning of the next (ie, in the interdialytic interval).
The importance of residual renal urea clearance was shown in a study of 36,757 incident hemodialysis patients, in which an nPCR variable was used to account for residual renal clearance [10]. Higher baseline renal urea clearance-corrected nPCR and a greater increase in renal urea clearance-corrected nPCR over time were independently associated with higher serum albumin levels and lower all-cause mortality. The authors concluded that nPCR may be underestimated when not accounting for renal urea clearance and, compared with the conventional nPCR, renal urea clearance–corrected nPCR may be a better marker of mortality.
Relationship between dialysis adequacy and protein catabolic rate — The PCR varies directly with the Kt/V, a measure of dialysis adequacy [4]. (See "Prescribing and assessing adequate hemodialysis".)
Patients who receive an inadequate amount of dialysis, as demonstrated by a low Kt/V, are often uremic and anorexic. As a result, they have a low protein intake and low PCR. Delivery of more dialysis as assessed by a higher Kt/V often improves appetite and increases protein intake, leading to higher PCR. As examples:
●In a study of a small group of hemodialysis patients, the intensity of dialysis was increased by increasing dialysis time, blood flow, and/or membrane surface area [11]. As the Kt/V rose from 0.82 to 1.32 over a three-month period, there was a concurrent increase in nPCR from 0.81 to 1.02 g/kg per day. A second group in which the dialysis regimen was unchanged had no increase in either Kt/V or nPCR.
●In another report, converting 13 patients from conventional dialysis (three times, four hours each week) to three times per week nocturnal dialysis (three times, eight hours each week) increased the Kt/V from 1.87 to 2.7 and the nPCR from 1.39 to 2.25 g/kg per day at 12 months [12].
The association between a low normalized protein nitrogen appearance (nPNA) and outcome could be attributable to the adverse effects of low Kt/V. However, one study reported that the amount of daily protein intake, expressed as nPCR, has an independent effect on morbidity and mortality in hemodialysis patients whose dialysis dose was considered adequate [4].
Limitations of protein catabolic rate — The use of PCR to estimate protein intake has a number of limitations [5,13]. These include the following:
●Patients must be in neutral nitrogen balance – The PCR reflects protein intake only in patients in neutral nitrogen balance (ie, steady state). Many dialysis patients are not in neutral nitrogen balance. The PCR overestimates dietary protein intake in patients who are catabolic, such as those with active inflammation. This is because there is an increase in endogenous nitrogen breakdown in such patients, which is reflected in the PCR. A rapid increase in PCR or a PCR over 1.4 g/kg/day is likely to be attributed to an increase in catabolic rate during infection or inflammation, especially if the PCR increase occurs in the setting of loss of weight and decline in serum albumin and creatinine [14].
Conversely, the PCR underestimates dietary protein intake in patients who are anabolic, such as those recovering from infection, growing children, or individuals in the last trimester of pregnancy. This is because dietary protein is utilized for build-up of new body protein pools and does not contribute to the appearance of nitrogen [13].
●PCR overestimates dietary protein intake when intake is low – The PCR may overestimate dietary protein intake when the protein intake is less than 1 g/kg/day, possibly due to endogenous protein catabolism [13]. One study showed that at progressively greater levels of C-reactive protein (CRP), serum albumin concentration decreased even if nPCR values were high [15]. The same authors also showed that nPCR may overestimate dietary protein intake because of endogenous nitrogen breakdown during inflammation [16].
●PCR fluctuates rapidly in response to daily protein intake – As a result of rapid fluctuations in PCR following changes in protein intake, individual values may reflect the most recent protein intake and not the patient’s usual diet [13]. In one study of 50 patients, for example, three measurements from a single individual were required to obtain a PCR with an error of less than 10 percent [17].
●The PCR underestimates dietary protein intake by a variable amount – The PCR accurately reflects the dietary protein intake only if the method used to calculate the PCR includes all the body nitrogen output, including losses into dialysate [5,18].
●PCR normalized to body weight may be misleading in obese, malnourished, or edematous patients – Normalization of PCR to body weight may be misleading in obese, malnourished, and edematous individuals because body weight can vary significantly over short periods of time. In addition, the nPCR can overestimate protein intake in malnourished patients and older adults with muscle wasting and underestimate protein intake in obese patients with increased fat mass. To address these limitations, it has been suggested that PCR should be normalized to lean body weight, which would directly couple PCR to changes in protein or nitrogen reserve [19].
TARGET PROTEIN CATABOLIC RATE — The optimal target normalized protein catabolic rate (nPCR) is >1.4 g/kg/day. However, this target is difficult to achieve. We suggest a minimum target nPCR of 1.2 g/kg/day. This is consistent with both the American Kidney Disease Outcomes Quality Initiative (KDOQI) clinical practice guidelines and the European Best Practice Guidelines on hemodialysis [7,20].
The recommendations also indicate that one-half of the daily protein intake should be of high biological value (ie, animal based) proteins. However, dialysis patients who consume vegetarian diets have also been able to attain an adequate amount of protein intake, estimated at 1.1 to 1.25 g/kg/day of protein [21]. Besides being adequate, a plant-based protein diet may provide additional benefits including better control of hypertension, hyperphosphatemia, and metabolic acidosis and reduced protein-bound uremic toxins such as indoxyl sulfate and p-cresyl sulfate [21,22].
Multiple studies have suggested that, compared with lower values, an nPCR between 1.0 and 1.4 is associated with lower mortality [23-25]. Perhaps the best data are from a retrospective, two-year study that evaluated time-varying dietary protein intake and survival among nearly 54,000 hemodialysis patients [25]. The best survival was noted with levels between 1.0 and 1.4 g/kg/day. However, a review of dietary protein intake studies in dialysis patients found that a majority of the studies published after the KDOQI guidelines became available still indicated suboptimal dietary protein intake in hemodialysis patients [26].
MONITORING AND INTERVENTION — Hemodialysis patients have a high dietary protein requirement but usually consume less than 1.0 g/kg/day of protein [27]. In order to avoid malnutrition and its accompanying poor outcomes, the protein catabolic rate (PCR) should be measured monthly along with the Kt/V and with other assessments of nutritional status. (See "Assessment of nutritional status in patients on hemodialysis", section on 'Laboratory assessment'.)
Patients with low PCR should receive nutritional counseling on a monthly basis to help maintain a minimum PCR of 1.2 g/kg. This goal may be achieved by dietary protein supplementation. In a 2020 meta-analysis of 22 trials and 1278 dialysis patients that compared oral protein-based nutritional supplementation with either no supplementation or with placebo, supplementation led to an increase in serum albumin (mean increase 0.2 g/dL, 95% CI 0.06 to 0.37), serum pre-albumin (mean increase 2.8 g/dL, 95% CI 2.2 to 3.4), and mid-arm muscle circumference (mean increase 1.3 cm, 95% CI 0.24 to 2.4) [28]. These changes were more pronounced among patients who were malnourished and patients who were receiving hemodialysis (compared with those receiving peritoneal dialysis). There was a slight increase in gastrointestinal intolerance among recipients of oral protein-based nutritional supplementation, but no increase in serum potassium or phosphate. PCR was not evaluated as an outcome and neither were patient-important endpoints (eg, mortality) in any of the included studies.
Adjustment of the dialysis prescription to raise the Kt/V can also lead to improvement in the PCR. However, among patients who have an adequate Kt/V, unless the PCR is very low (eg, <0.8 g/kg per day), the PCR should be followed over a number of months before the dialysis prescription is changed. As noted above, since the PCR fluctuates with day-to-day changes in the diet, individual PCR values often reflect the most recent protein intake and are not representative of the patient’s usual diet (see 'Limitations of protein catabolic rate' above). Determining the patient's usual protein intake may require several months of monitoring PCR.
Among patients who have a very low PCR (ie, <0.8 g/kg per day), other evidence of malnutrition, or a low Kt/V, the dialysis prescription should be immediately changed. (See "Assessment of nutritional status in patients on hemodialysis" and "Prescribing and assessing adequate hemodialysis".)
Several factors may contribute to the development of malnutrition:
●Inability of the patient to change from a protein-restricted diet (which is commonly followed by predialysis chronic kidney disease [CKD] patients) to a protein-rich diet after initiation of dialysis.
●Increased catabolism caused by the hemodialysis procedure. Eight to 10 grams of protein are lost with each hemodialysis treatment.
●Omission of meals on dialysis days due to time spent on dialysis.
●The misconception among clinicians that a patient with a minimally acceptable Kt/V and a low midweek blood urea nitrogen (BUN) is always well dialyzed. The PCR is often below the goal level in this setting as inadequate protein intake contributes to the low BUN.
●The presence of other complicating clinical and social issues, including gastrointestinal disorders, inadequate understanding of dietary instructions, poor dentition, alcoholism, depression, concomitant debilitating diseases, and insufficient income (high-biologic-value, protein-rich foods are expensive).
●An expert panel of the International Society of Renal Nutrition and Metabolism noted that depletion of protein or energy stores in kidney disease is not always related to nutrient intake but could also be a result of wasting induced by hypercatabolism from multiple factors, such as uremic toxins, inflammation, oxidative stress, and metabolic acidosis [29].
●Persistent metabolic acidosis, reflecting inadequate dialysis despite an acceptable Kt/V [30,31]. (See "Pathogenesis, consequences, and treatment of metabolic acidosis in chronic kidney disease".)
SUMMARY AND RECOMMENDATIONS
●The protein catabolic rate (PCR), also called the protein equivalent of nitrogen appearance (PNA), can be used to assess dietary protein intake in hemodialysis patients who are in a steady state. The PCR is used along with many other markers of nutritional status in hemodialysis patients. (See 'Introduction' above.)
●The PCR is determined by measuring the interdialytic appearance of urea in body fluids plus any urea lost in the urine in patients with residual kidney function. (See 'Introduction' above and 'Overview' above.)
●The PCR is usually expressed as g/kg body weight per day, a parameter that is also called the normalized PCR (nPCR). A simple calculation of nPCR requires only the pre- and post-blood urea nitrogen (BUN) and the calculated Kt/V obtained during a single dialysis session. Adjustments for unmeasured urinary urea losses must be made to the calculation if the patient has significant residual kidney function. (See 'Calculation' above.)
●The nPCR varies directly with the Kt/V, which is a marker of dialysis adequacy. As dialysis adequacy increases, protein intake (and thus nPCR) generally increases. However, the nPCR is independently associated with the morbidity and mortality of hemodialysis patient who are adequately dialyzed as expressed by Kt/V >1.2. (See 'Relationship between dialysis adequacy and protein catabolic rate' above.)
●The optimal target nPCR is >1.4 g/kg per day. However, this target is difficult to achieve. We target a goal nPCR of ≥1.2 g/kg per day. (See 'Target protein catabolic rate' above.)
●The PCR should be measured monthly along with other measures of nutritional adequacy. Intensive nutritional counseling by a renal dietitian should be done monthly to help maintain a minimum PCR of 1.2 g/kg per day. Oral protein-based supplements may be beneficial among patients who are malnourished. (See 'Monitoring and intervention' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Robert E Cronin, MD, and William L Henrich, MD, MACP, who contributed to earlier versions of this topic review.
